Sustained release of methantheline

ABSTRACT

A sustained release pharmaceutical composition which includes methantheline bromide; a polymer of a monomer mixture of a monoester of acrylic acid and/or methacrylic acid and a polyhydric alcohol; another monoethylenically unsaturated ester; and a diester of acrylic acid and/or methacrylic acid and a polyhydric alcohol; and a polymer of a monomer mixture of a monoester of acrylic and/or methacrylic acid and a polyhydric alcohol; a polymerizable sulfur containing material; and a diester of acrylic and/or methacrylic acid and a polyhydric alcohol.

United States Patent 1m Sim et al.

[ SUSTAINED RELEASE OF METHANTHELINE [73] Assignee: Union Corporation,Verona, Pa.

[22] Filed: Sept. I0, 1973 [Zll Appl. No: 395,786

(52] US. Cl 424/22; 424/81 [5 ll lnt. Cl? l l A61K 27/12 [58} Field ofSearch .i 424/l9-22, 424/8l [Sol References Cited UNITED STATES PATENTS133L798 7/[967 Hihhard 260/296 1412x154 3/l969 Hihbard l l l 4 4 260/296155L556 l2/|'-)7(l Kliment et all i o o o v l 424/21 3 577 5l2 5/l97lShepherd et ul 424/2l 3 6l 9 h34 9/1972 Kliment et al. 424/2] 145] Oct.7, 1975 ll/l973 Lehman et al .l 424/2l OTHER PUBLICATIONS Stecher ctali, Merck Index 8th Ed. I968, Merck & Co., Rahway, N]. p. 671 entryMethantheline Bro mide."

Primary ExaminerShcp K. Rose Attorney, Agent, or FirmPollock Philpitt &Vande Sande [57 1 ABSTRACT A sustained release pharmaceuticalcomposition which includes methantheline bromide; a polymer of a monomermixture of a monoester of acrylic acid and- /or methacrylic acid and apolyhydric alcohol; another monoethylenically unsaturated ester; and adiester of acrylic acid and/or methacrylic acid and a polyhydricalcohol; and a polymer of a monomer mixture of a monoester of acrylicand/or methucrylic acid and a polyhydric alcohol; a polymerizable sulfurcontaining material; and a diester of acrylic and/or moth-acrylic acidand a polyhydric alcohol.

[9 Claims, No Drawings SUSTAINED RELEASE OF METHANTHELINE BACKGROUND OFTHE INVENTION The present invention is concerned with a sustainedrelease pharmaceutical composition, and in particular is concerned witha sustained pharmaceutical composition which contains two differentwater-insoluble but water-swellable hydrophilic polymers of a monoesterof acrylic and/or methacrylic acid; another monoethylenicallyunsaturated ester. The present invention is also concerned with a methodfor preparing the pharmaceutical compositions.

It has previously been suggested to incorporate drugs into hydrophilicpolymers to provide sustained release of the drug. Although a widevariety of suitable polymers and applicable drugs have previously beensuggested, only a very limited number of conbinations of particulardrugs and particular polymers have to date been successful in providingsustained release characteristics.

In addition, the majority of the prior art combinations exhibit arelease profile which follows first order kinetics and a high initialrelease rate which decays rapidly as the concentration of the drug inthe polymer decreases.

Moreover, various prior suggested combinations have release rates whichare too fast for providing sufficiently long release times to be of anypractical significance.

It has become quite evident that not any combination of any drug and anyhydrophilic polymer will provide a sustained release pharmaceuticalcomposition. The preparation of sustained release pharmaceuticalcompositions from polymers and drugs is highly empirical. The art hasnot advanced to the stage where a person skilled in the art can predictwhether a particular combination of a drug and hydrophilic polymer willproduce a sustained release pharmaceutical composition.

Accordingly, it is an object of the present invention to provide asuitable sustained release pharmaceutical composition. It is a furtherobject of the present invention to provide a sustained releasepharmaceutical composition which releases the drug over a relativelylong period of time.

A further object of the present invention is to make it possible toobtain release of a drug which at least approaches zero order (i.e., asubstantially constant amount of release of the drug per unit time) forsome portion of the time during the treatment period.

SUMMARY OF THE INVENTION The present invention is concerned with asustained release multibarrier pharmaceutical composition comprising:

A. An outer matrix of a water-insoluble but waterswellable hydrophilicpolymer of a monomer mixture containing:

l. polymerizable monoester of acrylic and/or methacrylic acid and apolyhydric alcohol;

2. monoethylenically unsaturated ester selected from the groupconsisting of alkyl acrylates, alkyl methacrylates, vinyl esters ofsaturated monocarboxylic acids of up to 22 carbon atoms, and mixturesthereof, wherein the alkyl group of said methacrylate or acrylatecontains from I to 22 carbon atoms; and

3. polymerizable diester of acrylic and/or methacrylic acid and apolyhydric alcohol; and

wherein the monomer mixture contains from about 24 to about 65% byweight of (I); from about 34 to about by weight of (2); and from about0.1 to about l0% by weight of (3) based upon the total weight of l (2),and (3) in the monomer mixture;

B. An inner matrix within said outer matrix and being a water-insolublebut water-swellable hydrophilic polymer of a monomer mixture containing:

1. polymerizable monoester of acrylic and/or methacrylic acid and apolyhydric alcohol;

2. a polymerizable sulfur containing material selected from the groupconsisting of polymerizable ethylenically unsaturated organic sulfonicacids, ammonium salts thereof; alkali metal salts thereof; and mixturesthereof; and

3. polymerizable diester of acrylic and/or methacrylic acid and apolyhydric alcohol; and

wherein the monomer mixture contains from about 25 to about by weight of(1); from about 5 to about 45% by weight of 2); and from about 5 toabout 40% by weight of (3) based upon the total weight of (l), (2) and(3) in the monomer mixture; and

C. Methantheline bromide in an amount at least sufficient for the totaldosage requirement during a treatment period; and being entrapped insaid inner matrix.

The present invention is also concerned with a method for preparing thesustained release pharmaceutical composition which comprises:

A. entrapping the methantheline bromide in an inner matrix in an amountat least sufficient for the total dosage requirement during a treatmentperiod;

B. the inner matrix being a water-insoluble but waterswellablehydrophilic polymer of a monomer mixture containing 1. polymerizablemonoester of acrylic and/or methacrylic acid and a polyhydric alcohol;

2. a polymerizable sulfur containing material selected from the groupconsisting of polymerizable ethylenically unsaturated organic sulfonicacids; ammonium salts thereof; alkali metal salts thereof; and mixturesthereof; and

3. polymerizable diester of acrylic and/or methacrylic acid and apolyhydric alcohol; and wherein the monomer mixture contains from about25% to about 90% by weight of l from about 5 to about 45% by weight of(2); and from about 5 to about 40% of weight of (3) based upon the totalweight of l (2) and (3) in the monomer mixture;

C. grinding the resulting composition of the methantheline bromide andinner matrix into a powder;

D. admixing the powder and the monomeric mixture containing thepolymerizable monoester; other unsaturated ester and diester; and

E. then polymerizing to provide an outer matrix of the water-insolublebut water-swellable hydrophilic polymer of the monomer mixturecontaining the polymerizable monoester; other unsaturated ester anddiester.

DESCRIPTION OF PREFERRED EMBODIMENTS The polymerizable monoesters whichare suitable in obtaining the polymers of the outer matrix employed inthe present invention must be water-miscible. Such polymerizablemonoesters are monoesters of either acrylic and/or methacrylic acid anda polyhydric alcohol and preferably a dihydric alcohol. Suitabledihydric alcohols which may be employed to form the esters used in thepresent invention include among others ethylene glycol, 1,3-propanediol,the dialkylene glycols such as diethylene glycol and dipropylene glycol;and the polyalkylene glycols such as polyethlene glycol; and1,4-butanediol. Some suitable polyhydric alcohols which contain from 3to 6 alcohol groups and which may be employed to form the ester used inthe present invention include glycerol, trimethylol propane,trimethylolethane, pentaerylthritol, and hexitols such as mannitol andsorbitol. Examples of some suitable polymerizable monoesters include2-hydroxy ethyl methacrylate, 2-hydroxy ethyl acrylate, 2-hydroxy propylmethacrylate, diethylene glycol monomethacrylate, diethylene glycolmonoacrylate, Z-hydroxy propyl acrylate, 3-hydroxy propyl methacrylate,3-hydroxy propyl acrylate, dipropylene glycol monomethacrylate, glycerylmethacrylate, and pentaerythritol methacrylate, with the preferredpolymerizable monoester being 2- hydroxy ethyl methacrylate. The amountof polymerizable monoester employed in the monomeric mixture to preparethe polymers of the outer matrix is usually from about 24 to about 65%by weight, and is preferably from about 29 to about 55% by weight, basedupon the total weight of the polymerizable monoester, the otherunsaturated ester, and the diester. The most pre ferred amount ofmonoester is between about 33 and about 49.5% by weight based upon thetotal weight of the monoester, other unsaturated ester, and diester.

The other monoethylenically unsaturated ester which may be employed inpreparing the polymers employed in the outer matrix include the alkylmethacrylates, the alkyl acrylates, the vinyl esters of saturatedmonocarboxylic acids, and mixtures thereof.

Usually the alkyl radical of the methacrylate or acrylate contains up to22 carbon atoms, and preferably contains from 1 to carbon atoms. Someexamples of methacrylates suitable for use in the present inventioninclude methyl methacrylate, ethyl methacrylatc, isopropyl methacrylate,butyl methacrylate, capryl meth acrylate, palmityl methacrylate, stearylmethacrylate, and lauryl methacrylate. Some suitable acrylate estersinclude ethyl acrylate. methyl acrylate, isopropyl acrylate, butylacrylate, and lauryl acrylate.

The vinyl esters suitable in the present invention include the vinylesters of rnonocarboxylic acids wherein the acid contains up to about 22carbon atoms. Some suitable vinyl esters include vinyl acetate, vinylpropionate, vinyl butyrate, vinyl stearate, and the vinyl ester ofVersatic 91 1 acid which is a saturated synthetic tertiarymonocarbosylic acid having C, C and C chain length. The most preferredvinyl ester is vinyl acetate.

The preferred unsaturated esters employed in the outer matrix are themethacrylates of which the most preferred is methyl methacrylate. Theamount of unsaturated ester employed is usually between about 34 andabout 75% by weight, and preferably between about 40 and about 70% byweight based upon the total weight of the monoester, other unsaturatedester, and diester. The most preferred quantity of ester is betweenabout 49.5% and about 65% by weight based upon the total weight of themonoester, other unsaturated ester, and diester.

The polymerizable diesters employed in the outer matrix are diesters ofacrylic and/or methacrylic acid and a polyhydric alcohol and preferablya dihydric alcohol. Illustrative of such diesters are ethylene glycoldiacrylate, ethylene glycol dimethylacrylate, 1,2- butylenedimethacrylate, 1,3-buty1ene dimethacrylate, 1,4-butylenedimethacrylate, propylene glycol diacrylate, propylene glycoldimethacrylate, diethylene glycol dimethacrylate, dipropylene glycoldimethacrylate, diethylene glycol diacrylate, dipropylene glycoldiacrylate, tetraethylene glycol dimethacrylate, and tetraethyleneglycol diacrylate. The preferred diester is ethylene glycoldimethacrylate. The amount of diester employed is usually between about0.1 and about 10%, preferably between about 0.5 and 2%, and mostpreferably about l% by weight based upon the total weight of themonoester, other unsaturated ester, and diester.

The polymer of the outer matrix is usually present in amounts of about40 to about 90% by weight, preferably from about 50 to about by weight,and most preferably from about 65 to about 75% by weight based upon thetotal weight of the water insoluble but water swellable polymer of theouter matrix, the water insoluble but water swellable polymer of theinner matrix and the methantheline bromide.

The polymerizable monoesters which are suitable in obtaining thepolymers of the inner matrix are the same type of monoesters describedhereinabove for the polymers of the outer matrix.

The preferred polymerizable monoester for the polymers of the innermatrix is Z-hydroxyethyl methacrylate. The amount of polymerizablemonoester employed in the polymers of the inner matrix is usuallybetween about 25 and about by weight, and is preferably between about 30and about 56% by weight based upon the total weight of the monoester,sulfur containing compound, and diester in the monomer mixture. The mostpreferred quantity of ester is about 45% by weight based upon the totalweight of the monoester, sulfur containing material, and diester in themonomer mixture.

The polymerizable sulfur containing material employed in the polymers ofthe inner matrix include polymerizable ethylenically unsaturated organicsulfonic acids and/or ammonium salts thereof and/or alkali metal saltsthereof such as sodium and potassium salts thereof. Illustrative of somepolymerizable ethylenically unsaturated organic sulfonic acids includevinylsulfonic acid, vinylpropanesulfonic acid and styrene sulfonic acidssuch as p-vinylbenzene-sulfonic acid. The preferred acid isp-vinylbenzenesulfonic acid and the preferred polymerizable sulfurcontaining material is sodium p-vinylbenzenesulfonate.

The amount of polymerizable sulfur containing material is usuallybetween about 5 and about 45% by weight, and is preferably between about22 and 40% by weight, and is most preferably about 30% by weight basedupon the total weight of the monoester, sulfur containing material anddiester in the monomer mixture.

The polymerizable diesters which are suitable in obtaining the polymersof the inner matrix are the same type of diesters described hereinabovefor the polymers of the outer matrix. The preferred polymerizablediester for the polymers of the inner matrix is tetraethylene glycoldimethacrylate. The amount of polymerizable diester employed in thepolymers of the inner matrix is usually between about 5 and about 40% byweight, and is preferably between about 22 and about 30% by weight, andis most preferably about 25% by weight based upon the total weight ofthe monoester, sulfur containing material and diester.

The monomer mixture for obtaining the polymers suitable for use as theouter matrix contains from about 24 or from about 29 to about 49.3% byweight of the polymerizable ethylenically unsaturated monoester, fromabout 34 or from about 40 to about 64.6% by weight of themonoethylenically unsaturated ester; and from about 0.1 or from about0.5 to about 1% by weight of the polymerizable diester based upon thetotal weight of the polymerizable monoester, the monoethylenicallyunsaturated ester, and the polymerizable diester in the monomer mixturefor polymers of the outer matrix.

The monomer mixture for obtaining the polymers suitable for use as theinner matrix contains from about 25 or from about 30% to about 44.3% byweight of the polymerizable monoester; from about 5 or about 22 to about30% by weight of the polymerizable sulfurcontaining material; and fromabout 5 or about 22 to about 25.2% by weight of the polymerizablediester based upon the total weight of the polymerizable monoester,polymerizable sulfur-containing material and polymerizable diester inthe monomer mixture for polymers of the inner matrix.

The inner matrix is generally present in amounts of about 1 to 50% byweight, preferably about 5 to about 35% by weight and most preferablyfrom about to about 25% by weight based upon the total weight of thewater insoluble but water swellable polymer of the outer matrix, thewater insoluble but water swellable polymer of the inner matrix and themethantheline bromide.

The methantheline bromide is generally used in amounts of about 0.] toabout 50%, preferably from about 0.5 to about 20% and most preferablyfrom about 8 to about l57r by weight based upon the total weight of themethantheline bromide, water-insoluble but water-swellable hydrophilicpolymer of the outer matrix and the water-insoluble but water-swellablehydrophilic polymer of the inner matrix.

In addition, the pharmaceutical compositions of the present inventioncan include such other materials as plasticizers. inert fillers, andsuspending aids such as Cab O-Sil, and bentone for the methanthelinebromide.

Moreover, the compositions of the present invention can be furtherencapsulated by another polymeric or other film-forming substanceaccording to particular applications of the composition. Such auxiliaryencapsulating layers can be soluble or insoluble in aqueous medium, thesolubility or swelling being dependent or independent or pH and/or ionicstrength, and can be susceptible or nonsusceptible to enzymatic action.

The pharmaceutical compositions of the present invention can be preparedby first contacting the methantheline bromide with the water-insolublebut waterswellable polymer of the inner matrix such as by immersing thepolymer in a bath such as an aqueous bath of the drug to cause diffusionof the methantheline bromide into a polymer matrix. Generally themethantheline bromide is contacted with the polymer of the inner matrixfor at least about minutes to cause diffusion into the polymer matrix.Of course, this can vary greatly depending upon the relative amounts ofthe drug and inner matrix.

Also methantheline bromide can be entrapped in the inner matrix byadmixing the methantheline bromide or an aqueous solution thereof andthe monomeric mixture containing the polymerizable monoester,unsaturated sulfur containing compound, and diester; and then bypolymerizing to provide a matrix of the waterinsoluble butwater-swellable polymer entrapping methantheline bromide.

The resulting composition is then preferably ground into a fine powderto facilitate subsequent admixing with the monomeric compositioncontaining the poly merizable monoester, other unsaturated ester anddiester for the polymer of the outer matrix to provide a homogeneouscomposition. If the composition of the inner matrix and methanthelinebromide contains liquid materials such as water, it is desirable toremove the liquid by air evaporation or heat before the composition isground into a fine powder. After the composition is ground into a finepowder, it is preferably admixed with monomeric composition containingthe polymerizable monoester, other unsaturated ester and diester. Thenthe composition is polymerized to provide an outer matrix of thewater-insoluble but waterswellable hydrophilic polymer of the monomermixture containing the polymerizable monoester; other unsaturated esterand diester; an inner matrix within the outer matrix and being awater-insoluble but water-swellable hydrophilic polymer of the monomermixture containing the polymerizable monoester, sulfur containingcompound, and diester; and methantheline bromide entrapped in said innermatrix. In addition the compositions of the present invention can beprepared by encapsulating or coating the fine powder or the inner matrixand methantheline bromide with an already formed polymer of themonoester, other unsaturated ester and diester.

The water-swellable polymers employed both in the inner matrix and outermatrix generally can be prepared by employing bulk polymerizationtechniques. The term bulk polymerization" as used herein includes thosepolymerizations carried out in the absence of a solvent or dispensingliquid as well as those poly merizations carried out in the presence ofwater or water-soluble or polymer-soluble liquid swelling agents in suchamounts as not to significantly alter the nature of the polymerizationprocess.

The polymerization catalyst employed can be any of the catalysts whichare suitable in polymerizing com pounds containing ethylenicunsaturation and preferably are the free radical catalysts. Ofparticular interest are the peroxide catalysts. Some examples ofsuitable peroxide catalysts include hydrogen peroxide, benzoyl peroxide,tertbutyl peroctoate, phthalic peroxide, succinic peroxide, benzoylacetic peroxide, tert-butyl peroxy pivalate, coconut oil acid peroxide,lauric peroxide, stearic peroxide, oleic peroxide, tert-butylhydroperoxide, tetraline hydroperoxide, tert-butyl diperphthalatc,cumene hydroperoxide, tert-butyl perbenzoate, acetyl peroxide,2,4-dichlorobenzoyl peroxide, urea peroxide, caprylyl peroxide,p-chlorobenzoyl peroxide, ditert-butyl peroxide, 2,2-bis(tert-butylperoxy)- butane, hydroxyheptyl peroxide, the diperoxide of benzaldehyde;alkylperoxycarbonates such as diisobutylperoxy bicarbonate, di-secondarybutyl peroxy bicarbonate, and tert-butyl peroxyisopropylcarbonate,

and the like. The preferred catalyst is one which is effective atmoderately low temperatures such as at about 3090 C.

The amount of catalyst employed depends upon the type of catalyst systemused and is generally from about 0.01 to about parts by weight per 100parts of the monomer mixture, and preferably is from about 0.1 to about1 part by weight per l00 parts of the monomer mixture.

The polymerization is generally carried out at temperatures from aboutroom temperature to about 150 C. lt is generally preferred to initiatethe polymerization at relatively low temperatures such as from about 35to about 85 C and then to increase the temperature to about 90 to about150 C as the reaction proceeds and preferably after most of the reactionhas been completed. The most preferred initial temperature range ofpolymerization is between about 30 and 90 C.

Usually the polymerization is conducted under autogenous pressure in aclosed reaction vessel. However, any suitable means to preventsignificant evaporation of any of the monomers can be employed.

Generally, the polymerization is completed in about 1/2 to about 12hours and preferably is completed in about 4 to about 6 hours. It isunderstood, of course, that the time and temperature are inverselyrelated. That is, temperatures employed at the upper end of thetemperature range will provide polymerization processes which can becompleted near the lower end of the time range.

in addition, it may be desirable for the copolymers obtained from suchpolymerizations to be post cured at temperatures somewhat higher thanthose initially employed in the polymerization. Usually the temperaturesemployed in the post cure will range from about 90 to about 150 C. Twohours is usually more than sufficient for such a post curing operation.Preferably the post cure is completed in 2 to 4 hours.

The pharmaceutical compositions of the present invention can be utilizedfor oral ingestion, implantation, or external application to a mucousmembrane. The pharmaceutical compositions of the present invention canbe implanted subcutaneously, constitute a part of a prosthesis, or beinserted in a cavity of the human body, Upon application to the desiredpart of the body by the desired mode, the pharmaceutical compositions ofthe present invention provide sustained release of the pharmacologicalmaterial by diffusion through pores of the water-insoluble butwater-swellable polymeric matrices to the desired part of the body uponcontact with body fluids.

The present invention makes it possible to obtain a sustained releasepharmaceutical composition which provides sustained release of themethantheline bromide over a relatively long period of time.

In addition, the present invention makes it possible to obtain asustained release of the methantheline bromide which approaches zeroorder release during portions of the treatment period, and therefore,can be considered to be pseudo zero order or substantially zero orderrelease. In addition, the sustained release characteristics of thepresent invention could not be predicted particularly since the polymersemployed in this invention did not always provide sustained releasecompositions. Moreover when methantheline bromide is employed togetherwith other polymers, a sustained release composition is not alwaysobtained.

The following examples are presented to further illustrate the presentinvention. All parts are by weight unless the contrary is stated.

EXAMPLE 1 A polymeric composition is prepared by admixing about 20 partsof water, and about 100 parts of a polymerizable composition containingabout 44.3% by weight of 2-hydroxyethylmethacrylate, about 30% by weightof sodium p-vinylbenzenesulfonate, about 25.2% of tetraethylene glycoldimethacrylate, and about 0.5% of tert-butyl peroctoate. The mixture isheated to 50 C for about 12 hours under a nitrogen atmosphere of 20 psito effect polymerization. The mixture is post-cured by heating underatmospheric pressure at C for 2 hours.

The resulting polymeric composition is soaked for about 12 hours atambient temperature in 5000 parts of isotonic saline solution (0.9%NaCl) containing 100 mg of methantheline bromide per 5 ml of salinesolution. The composition is then dried by heating under atmosphericpressure at C for about 3 hours. The dried composition is ground into afine powder by a mortar and pestle. 29.7 parts of the composition whichcontains about 18.4 parts of the polymer matrix and about 11.3 parts ofthe methantheline bromide are admixed with about 70.3 parts of apolymerizable composition containing about 49.3% by weight ofZ-hydroxymethylmethacrylate; about 49.3% by weight ofmethylmethacrylate, about 1% by weight of ethylene glycol dimethacrylateand about 0.4% by weight of tert butyl peroctoate. The mixture is heatedto 75 C for about 2 hours under a nitrogen atmosphere of 10 psi toeffect polymerization. The mixture is post-cured by heating underatmospheric pressure at C for 2 hours.

The above composition is introduced into a beaker containing 20milliliters of isotonic saline solution (0.9% NaCl) and the beaker isshaken at a constant temperature of 37 C in a thermostatic water bathshaker. The concentration of eluted methantheline is determined with aBeckman DB-GT spectrophotometer using the maximum absorption ofmethantheline bromide at 282 nanometers. Elution rates are checked atthe time intervals shown below and fresh isotonic saline is employedafter each reading. The results are listed below.

EXAMPLE 2 Example 1 is repeated except that the composition is obtainedfrom about 20.4 parts of the polymer of the inner matrix, about 12.5parts of methantheline bromide, and about 67.1 parts of the polymer ofthe outer matrix, and the outer matrix is a polymer obtained from apolymerizable mixture of about 33% by weight of2-hydroxyethylmethacrylate; about 64.6% by weight of methylmetnacrylate, about 1% by weight of ethylene glycol dimethacrylate, andabout 0.4% by weight of tert butyl peroctoate. The results are listedbelow.

mg of Methantheline mg of Methanthcline What is claimed is:

l. A sustained release 846 hour after administration methanthelineeluting multibarrier pharmaceutical composition comprising:

A. a polymerized and cured outer matrix of a waterinsoluble butwater-swellable hydrophilic polymer of a monomer mixture containing:

1. polymerizable monoester of a member selected from the groupconsisting of acyrlic acid, methacrylic acid, and mixtures thereof; anda polyhydric alcohol;

2. monoethylenically unsaturated ester selected from the groupconsisting of alkyl acrylates, alkyl methacrylates, vinyl esters ofsaturated monocarboxylic acids of up to 22 carbon atoms, and mixturesthereof, wherein the alkyl group of said methacrylate or acrylatecontains from 1 to 22 carbon atoms; and

3. polymerizable diester of a member selected from the group consistingof acrylic acid, methacrylic acid, and mixtures thereof; and polyhydricalcohol; and

wherein the monomer mixture contains from about 24 to about 49.3% byweight (A) (1); from about 34 to about 64.6% by weight of (A) (2); andfrom about 0.1

to about 1% by weight of (A) (3) based upon the total weight of (A) (1),(A) (2), and (A) (3) in the monomer mixture;

13. a polymerized and cured inner matrix within said outer matrix andbeing a water-insoluble but waterswellable hydrophilic polymer of amonomer mixture containing:

1. polymerizable monoester of a member selected from the groupconsisting of acrylic acid, methacrylic acid, and mixtures thereof; anda polyhydric alcohol;

2. a polymerizable sulfur-containing material selected from the groupconsisting of vinyl sulfonic acid, vinylpropane sulfonic acid, andstyrene sulfonic acids. ammonium salts thereof; alkali metal saltsthereof; and mixtures thereof; and

3. polymerizable diester of a member selected from the group consistingof acrylic acid, methacrylic acid. and mixtures thereof; and apolyhydric alcohol; and

wherein the monomer mixture contains from about 25 to about 44.3% byweight of (B) (1); from about 5 to about 30% by weight of (B) (2); andfrom about 5 to about 25.2% by weight of (B) (3) based upon the totalweight of(B) (1), (B) (2), and (B) (3) in the monomer mixture; and C.said polymerized and cured inner matrix having been soaked for about 12hours in isotonic saline solution containing per 5 ml of isotonic salinesolution at least about mg of methantheline bromide in an amount atleast sufficient for the total dosage requirement adapted to graduallyelute, upon administration during 864 hours of a treatment period; andthereby entrapping the methantheline bromide in said inner matrix.

2. The composition of claim 1 wherein each of said polymerizablemonoesters (A) (l) and (B) (l) is selected from the group consisting of2-hydroxy ethyl methacrylate, Z-hydroxy ethyl acrylate, 2-hydroxy propylmethacrylate, diethylene glycol monomethacrylate, diethylene glycolmonoacrylate, 2-hydroxy propyl acrylate, 3-hydroxy propyl methacrylate,3-.hydroxy propyl acrylate, dipropylene glycol monomethacrylate,glyceryl methacrylate, and pentaerythritol methacrylate.

3. The composition of claim 1, wherein each of said monoesters (A) (1)and (B) (l is 2-hydroxy ethyl methacrylate.

4. The composition of claim 1 wherein said monoethylenically unsaturatedester (A) (2) is selected from the group consisting of methylmethacrylate, ethyl methacrylate, isopropyl methacrylate, butylmethacrylate, capryl methacrylate, palmityl methacrylate, stearylmethacrylate, lauryl methacrylate, ethyl acrylate, methyl acrylate,isopropyl acrylate, butyl acrylate, lauryl acrylate, vinyl acetate,vinyl propionate, vinyl butyrate, vinyl stearate, and the vinyl ester ofa saturated tertiary monocarboxylic acid having C Cu). and C chainlength.

5. The composition of claim 1 wherein said monoethylenically unsaturatedester (A) (2) is methylmethacrylate.

6. The composition of claim 1 wherein each of said diesters (A) (3) and(B) (3) is selected from the group consisting of ethylene glycoldiacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate,1,3- butylene dimethacrylate, 1,4-butylene dimethacrylate, propyleneglycol diacrylate, propylene glycol dimethacrylate, diethylene glycoldimethacrylate, dipropylene glycol dimethacrylate, diethylene glycoldiacrylate, dipropylene glycol diacrylate, tetraethylene glycoldimethacrylate, and tetraethylene glycol diacrylate.

7. The composition of claim 1 wherein said diester (A) (3) is ethyleneglycol dimethacrylate and said diester (B) (3) is tetraethylene glycoldimethacrylate.

8. The composition of claim 1 wherein said polymerizablesulfur-containing material is selected from the group consisting ofstyrene sulfonic acids, ammonium salts thereof, alkali metal saltsthereof, and mixtures thereof,

9. The composition of claim 1 wherein said polymerizablesulfur-containing material is sodium pvinylbenzene sulfonic acid.

10. The composition of claim I wherein the monomer mixture of the outermatrix contains from about 29 to about 49.37r by weight of(A) l fromabout 40 to about 64.6% by weight of (A) (2); and from about 0.5 toabout 1% by weight of (A) (3) based upon the total weight of (A) (1 (A)(2), and (A) (3) in said monomer mixture; and wherein the monomermixture of the inner matrix contains from about 30 to about 44.3% byweight of (B) (1); from about 22 to about 30% by weight of (B) (2); andfrom about 22 to about 25.2% by weight of(B) (3) based upon the totalweight of (B) (l), (B) (2). and (B) (3) in the monomer mixture of theinner matrix.

11. The composition of claim 1 wherein each of said polymerizablemonoesters (A) (l) and (B) (l) is a monoester of a member selected fromthe group consisting of acrylic acid, methacrylic acid, and mixturesthereof, and a polyhydric alcohol selected from the group consisting ofethylene glycol, 1,3-propanediol, diethylene glycol, dipropylene glycol.polyethylene glycol, polypropylene glycol, 1,6-hexamethylene glycol,l,4-butanediol, glycerol, trimethylol propane, trimethylolethane,pentaerythritol, mannitol, and sorbitol.

12. The composition fo claim 1 wherein each of said polymerizablemonoesters (A) (1) and (B) (I) is a monoester of a member selected fromthe group consisting of acrylic acid, methacrylic acid, and mixturesthereof; and a polyhydric alcohol selected from the group consisting ofethylene glycol, 1,3-propanediol, diethylene glycol, dipropylene glycol,polyethylene glycol, polypropylene glycol, 1,6-hexamethylenc glycol,1,4-butanedio1, glycerol, trimethylol propane, trimethylolethane,pentaerythritol, mannitol, and sorbitol; wherein said polymerizablesulfur-containing material (B) (2) is selected from the group consistingof styrene sulfonic acids, ammonium salts thereof, alkali metal saltsthereof, and mixtures thereof; and wherein each of said diesters (A) (3and (B) (3) is selected from the group consisting of ethylene glycoldiacrylate, ethylene glycol dimethacrylate, 1,2-butylene dimethacrylate,1,3-butylene dimethacrylate, 1,4-butylene dimethacrylate, propyleneglycol diacrylate, propylene glycol dimethacrylate, diethylene glycoldimethacrylate, dipropylene glycol dimethacrylate, diethylene glycoldiacrylate, dipropylene glycol diacrylate, tetraethylene glycoldimethacrylate, and tetraethylene glycol diacrylate, and where saidmonoethylenically unsaturated ester (A) (2) is selected from the groupconsisting of methyl methacrylate, ethyl methacrylate, isopropylmethacrylate, butyl methacrylatc, capryl methacrylate, palmitylmethacrylate, stearyl methacrylate, lauryl methacrylate, ethyl acrylate,methyl acrylate, isopropyl acrylate, butyl acrylate, lauryl acrylate,vinyl acetate, vinyl propionatc, vinyl butyrate, vinyl stearate, and thevinyl ester of a saturated synthetic tertiary monocarboxylic acid havingC C and C chain length.

13. The composition of claim 12 wherein each of said polymerizablemonoesters (A) (l) and (B) (l) is selected from the group consisting ofZ-hydroxy ethyl methacrylate, 2-hydroxy ethyl acrylate, Z-hydroxy propylmethacrylatc, diethylene glycol monomethacrylate, diethylene glycolmonoacrylate, 2'hydroxy propyl acrylate, 3-hydroxy propyl methacrylate,3-hydroxy propyl acrylate, dipropylene glycol monomethacrylate,

glyccryl methacrylate, and pentaerythritol methacry late.

14. The composition of claim 13 wherein the monomer mixture of the outermatrix contains from about 29 to about 35% by weight of (A) l from about40 to about 64.6?! by weight of (A) (2); and from about 0.5 to about 1%by weight of (A) (3) based upon the total weight of(A) (l), (A) (2), and(A) (3) in said monomer mixture; and wherein the monomer mixture of theinner matrix contains from about 30 to about 44.3% by weight of (B) (1);from about 22 to about 30% by weight of (B) (2); and from about 22 toabout 25.2% by weight of B) (3) based upon the total weight of (B) (l),(B) (2), and (B) (3) in the monomer mixture of the inner matrix.

15. The composition of claim 1 wherein each of said monoesters (A) l)and (B) (l is Z-hydroxy ethyl methacrylate, said sulfur-containingmonomer (B) (2) is sodium p-toluene sulfonic acid; said diester (A) (2)is ethylene glycol dimethacrylate; said diester (B) (3) is tetraethylencglycol dimethacrylate, and said monoethylenically unsaturated ester (A)(2) is methyl methacrylate.

16. The composition of claim 15 wherein the monomer mixture of the outermatrix contains from about 29 to about 49.3% by weight of (A) (1), fromabout 40 to about 64.6% by weight of (A) (2); and from about 0.5 toabout 1% by weight of (A) (3) based upon the total weight of(A) (1), (A)(2), and (A) (3) in said monomer mixture; and wherein the monomermixture of the inner matrix contains from about 30 to about 44.3% byweight of (B) (1); from about 22 to about 30% by weight of (B) (2); andfrom about 22 to about 25.2% by weight of(B) (3) based upon the totalweight of B) (1), (B) (2), and (B) (3) in the monomer mixture of theinner matrix.

17. The composition of claim 1 wherein the outer matrix is present in anamount from about 50 to about 80% by weight and said inner matrix ispresent in an amount from about 5 to about 35% by weight based upon thetotal weight of said outer matrix, said inner matrix, and saidmethantheline bromide in the composition.

18. The composition of claim 1 wherein the outer matrix is present in anamount from about to about by weight and said inner matrix is present inan amount from about 10 to about 25% by weight of said outer matrix,said inner matrix, and said methantheline bromide in the composition.

19. The method for preparing the sustained release pharmaceuticalcomposition of claim 1 which comprises:

A. entrapping the methanthcline bromide in an inner matrix in an amountat least sufficient for the total dosage requirement during a treatmentperiod;

B. the inner matrix being a water-insolub1e but waterswellablehydrophilic polymer of a monomer mixture containing:

1. polymerizablc monoester of a member selected from the groupconsisting of acrylic acid, methacrylic acid, and mixtures thereof, anda polyhydric alcohol;

2. a polymerizable sulfur-containing material selected from the groupconsisting of vinyl sulfonic acid, vinylpropane sulfonic acid, andstyrene, sulfonic acids, ammonium salts thereof, alkali metal saltsthereof; and mixtures thereof; and

3. polymerizable diester of a member selected from the group consistingof acrylic acid, methacrylic acid, and mixtures thereof; and apolyhydric alcohol; and

wherein the monomer mixture contains from about 25 to about 44.3% byweight of (B) (l from about to about 30% by weight of (B) (2); and fromabout 5 to about 25.2% by weight of(B) (3) based upon the total weightof(B) l (B) (2), and (B) (3) in the monomer mixture;

C. grinding the resulting composition of the methantheline bromide andinner matrix into a powder;

D. admixing said powder and a polymerizable monomer mixture containing:

1. polymerizable monoester of a member selected from the groupconsisting of acrylic acid, methacrylic acid, and mixtures thereof; anda polyhydric alcohol;

2. monethylenically unsaturated ester selected from the group consistingof alkyl acrylates, alkyl methacrylates, vinyl esters of saturatedmonocarboxylic acids of up to 22 carbon atoms, and mixtures thereof,wherein the alkyl group of said methacrylates or acrylates contains fromI to 22 carbon atoms; and 3. polymerizable diester of a member selectedfrom the group consisting of acrylic acid, methacrylic acid, andmixtures thereof; and a polyhydric alco hol; and wherein the monomermixture contains from about 24 to about 49.3% by weight of(D) l fromabout 34 to about 64.6% by weight of (D) (2); and from about 0. l toabout by weight of (D) (3) based upon the total weight of(D) (l), (D)(2), and (D) (3) in said monomer mixture; and E. then polymerizing toprovide an outer matrix of the water-insoluble but water-swellablehydrophilic polymer of the monomer mixture containing the polymerizablemonoester and diester.

1. A SUSTAINED RELEASE 846 HOUR AFTER ADMINISTRATION METHANTHELINEELUTING MULTIBARRIER PHARMACEUTICAL COMPOSITION COMPRISING: A. APOLYMERIZED AND CURED OUTER MATRIX OF A WATER-INSOLUBLE BUTWATER-SWELLABLE HYDROPHILIC POLYMER OF A MONOMER MIXTURE CONTAINING: 1.POLYMERIZABLE MONOESTER OF A MEMBER SELECTED FROM THE GROUP CONSISTINGOF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURES THEREOF, AND APOLYHYDRIC ALCOHOL.
 1. POLYMERIZABLE MONOESTER OF A MEMBER SELECTED FROMTHE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURESTHEREOF, AND A POLYHYDRIC ALCOHOL,
 2. A POLYMERIZABLE SULFUR-CONTAININGMATERIAL SELECTED FROM THE GROUP CONSISTING OF VINYL SULFONIC ACID,VINYLPROPANE SULFONIC ACID, AND STYRENE SULFONIC ACIDS, AMMONIUM SALTSTHEREOF, ALKALI METAL SALTS THEREOF, AND MIXTURES THEREOF, AND 2.monethylenically unsaturated ester selected from the group consisting ofalkyl acrylates, alkyl methacrylates, vinyl esters of saturatedmonocarboxylic acids of up to 22 carbon atoms, and mixtures thereof,wherein the alkyl group of said methacrylates or acrylates contains from1 to 22 carbon atoms; and
 2. MONOETHYLENICALLY UNSATURATED ESTERSELECTED FROM THE GROUP CONSISTING OF ALKYL ACRYLATES, ALKYLMETHACRYLATES, VINYL ESTERS OF SATURATED MONOCARBOXYLIC ACIDS OF UP TO22 CARBON ATOMS, AND MIXTURES THEREOF, WHEREIN THE ALKYL GROUP OF SAIDMETHYACRYLATE OR ACRYLATE CONTAINS FROM 1 TO 22 CARBON ATOMS, AND
 2. apolymerizable sulfur-containing material selected from the groupconsisting of vinyl sulfonic acid, vinylpropane sulfonic acid, andstyrene, sulfonic acids, ammonium salts thereof, alkali metal saltsthereof; and mixtures thereof; and
 2. The composition of claim 1 whereineach of said polymerizable monoesters (A) (1) and (B) (1) is selectedfrom the group consisting of 2-hydroxy ethyl methacrylate, 2-hydroxyethyl acrylate, 2-hydroxy propyl methacrylate, diethylene glycolmonomethacrylate, diethylene glycol monoacrylate, 2-hydroxy propylacrylate, 3-hydroxy propyl methacrylate, 3-hydroxy propyl acrylate,dipropylene glycol monomethacrylate, glyceryl methacrylate, andpentaerythritol methacrylate.
 2. a polymerizable sulfur-containingmaterial selected from the group consisting of vinyl sulfonic acid,vinylpropane sulfonic acid, and styrene sulfonic acids, ammonium saltsthereof; alkali metal salts thereof; and mixtures thereof; and 2.monoethylenically unsaturated ester selected from the group consistingof alkyl acrylates, alkyl methacrylates, vinyl esters of saturatedmonocarboxylic acids of up to 22 carbon atoms, and mixtures thereof,wherein the alkyl group of said methacrylate or acrylate contains from 1to 22 carbon atoms; and
 3. POLYMERIZABLE DIESTER OF A MEMBER SELECTEDFROM THE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, ANDMIXTURES THEREOF, AND A POLYHYDRIC ALCOHOL, AND WHEREIN THE MONOMERMIXTURE CONTAINS FROM ABOUT 25 TO ABOUT 44.3% BY WEIGHT OF (B) (1), FROMABOUT 5 TO ABOUT 30% BY WEIGHT OF (B) (2), AND FROM ABOUT 5 TO ABOUT25.2% BY WEIGHT OF (B) (3) BASED UPON THE TOTAL WEIGHT OF (B) (1), (B)(2), AND (B) (3) IN THE MONOMER MIXTURE, AND C. SAID POLYMERIZED ANDCURED INNER MATRIX HAVING BEEN SOAKED FOR ABOUT 12 HOURS IN ISOTONICSALINE SOLUTION CONTAINING PER 5 ML OF ISOTONIC SALINE SOLUTION AT LEASTABOUT 100 MG OF METHANTHELINE BROMINE IN AN AMOUNT AT LEAST SUFFICIENTFOR THE TOTAL DOSAGE REQUIREMENT ADAPTED TO GRADUALLY ELUTE, UPONADMINISTRATION DURING 864 HOURS OF A TREATMENT PERIOD, AND THEREBYENTRAPPING THE METHANTHELINE BROMIDE IN SAID INNER MATRIX. 3.polymerizable diester of a member selected from the group consisting ofacrylic acid, methacrylic acid, and mixtures thereof; and polyhydricalcohol; and wherein the monomer mixture contains from about 24 to about49.3% by weight (A) (1); from about 34 to about 64.6% by weight of (A)(2); and from about 0.1 to about 1% by weight of (A) (3) based upon thetotal weight of (A) (1), (A) (2), and (A) (3) in the monomer mixture; B.a polymerized and cured inner matrix within said outer matrix and beinga water-insoluble but water-swellable hydrophilic polymer of a monomermixture containing:
 3. polymerizable diester of a member selected fromthe group consisting of acrylic acid, methacrylic acid, and mixturesthereof; and a polyhydric alcohol; and wherein the monomer mixturecontains from about 25 to about 44.3% by weight of (B) (1); from about 5to about 30% by weight of (B) (2); and from about 5 to about 25.2% byweight of (B) (3) based upon the total weight of (B) (1), (B) (2), and(B) (3) in the monomer mixture; and C. said polymerized and cured innermatrix having been soaked for about 12 hours in isotonic saline solutioncontaining per 5 ml of isotonic saline solution at least about 100 mg ofmethantheline bromide in an amount at least sufficient for the totaldosage requirement adapted to gradually elute, upon administrationduring 864 hours of a treatment period; and thereby entrapping themethantheline bromide in said inner matrix.
 3. The composition of claim1, wherein each of said monoesters (A) (1) and (B) (1 ) is 2-hydroxyethyl methacrylate.
 3. POLYMERIZABLE DIESTER OF A MEMBER SELECTED FROMTHE GROUP CONSISTING OF ACRYLIC ACID, METHACRYLIC ACID, AND MIXTURESTHEREOF, AND POLYHYDRIC ALCOHOL, AND WHEREIN THE MONOMER MIXTURECONTAINS FROM ABOUT 24 TO ABOUT 49.3% BY WEIGHT (A) (1), FROM ABOUT 34TO ABOUT 64.6% BY WEIGHT OF (A) (2), AND FROM ABOUT 0.1 TO ABOUT 1% BYWEIGHT OF (A) (3) BASED UPON THE TOTAL WEIGHT OF (A) (1), (A) (2), AND(A) (3) IN THE MONOMER MIXTURE, B. A POLYMERIZED AND CURED INNER MATRIXWITHIN SAID OUTER MATRIX AND BEING A WATER-INSOLUBLE BUT WATER-SWELLABLEHYDROPHILIC POLYMER OF A MONOMER MIXTURE CONTAINING:
 3. polymerizablediester of a member selected from the group consisting of acrylic acid,methacrylic acid, and mixtures thereof; and a polyhydric alcohol; andwherein the monomer mixture contains from about 24 to about 49.3% byweight of (D) (1); from about 34 to about 64.6% by weight of (D) (2);and from about 0.1 to about % by weight of (D) (3) based upon the totalweight of (D) (1), (D) (2), and (D) (3) in said monomer mixture; and E.then polymerizing to provide an outer matrix of the water-insoluble butwater-swellable hydrophilic polymer of the monomer mixture containingthe polymerizable monoester and diester.
 3. polymerizable diester of amember selected from the group consisting of acrylic acid, methacrylicacid, and mixtures thereof; and a polyhydric alcohol; and wherein themonomer mixture contains from about 25 to about 44.3% by weight of (B)(1); from about 5 to about 30% by weight of (B) (2); and from about 5 toabout 25.2% by weight of (B) (3) based upon the total weight of (B) (1),(B) (2), and (B) (3) in the monomer mixture; C. grinding the resultingcomposition of the methantheline bromide and inner matrix into a powder;D. admixing said powder and a polymerizable monomer mixture containing:4. The composition of claim 1 wherein said monoethylenically unsaturatedester (A) (2) is selected from the group consisting of methylmethacrylate, ethyl methacrylate, isopropyl methacrylate, butylmethacrylate, capryl methacrylate, palmityl methacrylate, stearylmethacrylate, lauryl methacrylate, ethyl acrylate, methyl acrylate,isopropyl acrylate, butyl acrylate, lauryl acrylate, vinyl acetate,vinyl propionate, vinyl butyrate, vinyl stearate, and the vinyl ester ofa saturated tertiary monocarboxylic acid having C9, C10, and C11 chainlength.
 5. The composition of claim 1 wherein said monoethylenicallyunsaturated ester (A) (2) is methylmethacrylate.
 6. The composition ofclaim 1 wherein each of said diesters (A) (3) and (B) (3) is selectedfrom the group consisting of ethylene glycol diacrylate, ethylene glycoldimethacrylate, 1,2-butylene dimethacrylate, 1,3-butylenedimethacrylate, 1,4-butylene dimethacrylate, propylene glycoldiacrylate, propylene glycol dimethacrylate, diethylene glycoldimethacrylate, dipropylene glycol dimethacrylate, diethylene glycoldiacrylate, dipropylene glycol diacrylate, tetraethylene glycoldimethacrylate, and tetraethylene glycol diacrylate.
 7. The compositionof claim 1 wherein said diester (A) (3) is ethylene glycoldimethacrylate and said diester (B) (3) is tetraethylene glycoldimethacrylate.
 8. The composition of claim 1 wherein said polymerizablesulfur-containing material is selected from the group consisting ofstyrene sulfonic acids, ammonium salts thereof, alkali metal saltsthereof, and mixtures thereof.
 9. The composition of claim 1 whereinsaid polymerizable sulfur-containing material is sodium p-vinylbenzenesulfonic acid.
 10. The composition of claim 1 wherein the monomermixture of the outer matrix contains from about 29 to about 49.3% byweight of (A) (1); from about 40 to about 64.6% by weight of (A) (2);and from about 0.5 to about 1% by weight of (A) (3) based upon the totalweight of (A) (1), (A) (2), and (A) (3) in said monomer mixture; andwherein the monomer mixture of the inner matrix contains from about 30to about 44.3% by weight of (B) (1); from about 22 to about 30% byweight of (B) (2); and from about 22 to about 25.2% by weight of (B) (3)based upon the total weight of (B) (1), (B) (2), and (B) (3) in themonomer mixture of the inner matrix.
 11. The composition of claim 1wherein each of said polymerizable monoesters (A) (1) and (B) (1) is amonoester of a member selected from the group consisting of acrylicacid, methacrylic acid, and mixtures thereof, and a polyhydric alcoholselected from the group consisting of ethylene glycol, 1,3-propanediol,diethylene glycol, dipropylene glycol, polyethylene glycol,polypropylene glycol, 1,6-hexamethylene glycol, 1,4-butanediol,glycerol, trimethylol propane, trimethylolethane, pentaerythritol,mannitol, and sorbitol.
 12. The composition fo claim 1 wherein each ofsaid polymerizable monoesters (A) (1) and (B) (1) is a monoester of amember selected from the group consisting of acrylic acid, methacrylicacid, and mixtures thereof; and a polyhydric alcohol selected from thegroup consisting of ethylene glycol, 1,3-propanediol, diethylene glycol,dipropylene glycol, polyethylene glycol, polypropylene glycol,1,6-hexamethylene glycol, 1,4-butanediol, glycerol, trimethylol propane,trimethylolethane, pentaerythritol, mannitol, and sorbitol; wherein saidpolymerizable sulfur-containing material (B) (2) is selected from thegroup consisting of styrene sulfonic acids, ammonium salts thereof,alkali metal salts thereof, and mixtures thereof; and wherein each ofsaid diesters (A) (3) and (B) (3) is selected from the group consistingof ethylene glycol diacrylate, ethylene glycol dimethacrylate,1,2-butylene dimethacrylate, 1,3-butylene dimethacrylate, 1,4-butylenedimethacrylate, propylene glycol diacrylate, propylene glycoldimethacrylate, diethylene glycol dimethacrylate, dipropylene glycoldimethacrylate, diethylene glycol diacrylate, dipropylene glycoldiacrylate, tetraethylene glycol dimethacrylate, and tetraethyleneglycol diacrylate, and where said monoethylenically unsaturated ester(A) (2) is selected from the group consisting of methyl methacrylate,ethyl methacrylate, isopropyl methacrylate, butyl methacrylate, caprylmethacrylate, palmityl methacrylate, stearyl methacrylate, laurylmethacrylate, ethyl acrylate, methyl acrylate, isopropyl acrylate, butylacrylate, lauryl acrylate, vinyl acetate, vinyl propionate, vinylbutyrate, vinyl stearate, and the vinyl ester of a saturated synthetictertiary monocarboxylic acid having C9, C10, and C11 chain length. 13.The composition of claim 12 wherein each of said polymerizablemonoesters (A) (1) and (B) (1) is selected from the group consisting of2-hydroxy ethyl methacrylate, 2-hydroxy ethyl acrylate, 2-hydroxy propylmethacrylate, diethylene glycol monomethacrylate, diethylene glycolmonoacrylate, 2-hydroxy propyl acrylate, 3-hydroxy propyl methacrylate,3-hydroxy propyl acrylate, dipropylene glycol monomethacrylate, glycerylmethacrylate, and pentaerythritol methacrylate.
 14. The composition ofclaim 13 wherein the monomer mixture of the outer matrix contains fromabout 29 to about 35% by weight of (A) (1); from about 40 to about 64.6%by weight of (A) (2); and from about 0.5 to about 1% by weight of (A)(3) based upon the total weight of (A) (1), (A) (2), and (A) (3) in saidmonomer mixture; and wherein the monomer mixture of the inner matrixcontains from about 30 to about 44.3% by weight of (B) (1); from about22 to about 30% by weight of (B) (2); and from about 22 to about 25.2%by weight of (B) (3) based upon the total weight of (B) (1), (B) (2),and (B) (3) in the monomer mixture of the inner matrix.
 15. Thecomposition of claim 1 wherein each of said monoesters (A) (1) and (B)(1) is 2-hydroxy ethyl methacrylate, said sulfur-containing monomer (B)(2) is sodium p-toluene sulfonic acid; said diester (A) (2) is Ethyleneglycol dimethacrylate; said diester (B) (3) is tetraethylene glycoldimethacrylate, and said monoethylenically unsaturated ester (A) (2) ismethyl methacrylate.
 16. The composition of claim 15 wherein the monomermixture of the outer matrix contains from about 29 to about 49.3% byweight of (A) (1); from about 40 to about 64.6% by weight of (A) (2);and from about 0.5 to about 1% by weight of (A) (3) based upon the totalweight of (A) (1), (A) (2), and (A) (3) in said monomer mixture; andwherein the monomer mixture of the inner matrix contains from about 30to about 44.3% by weight of (B) (1); from about 22 to about 30% byweight of (B) (2); and from about 22 to about 25.2% by weight of (B) (3)based upon the total weight of (B) (1), (B) (2), and (B) (3) in themonomer mixture of the inner matrix.
 17. The composition of claim 1wherein the outer matrix is present in an amount from about 50 to about80% by weight and said inner matrix is present in an amount from about 5to about 35% by weight based upon the total weight of said outer matrix,said inner matrix, and said methantheline bromide in the composition.18. The composition of claim 1 wherein the outer matrix is present in anamount from about 65 to about 75% by weight and said inner matrix ispresent in an amount from about 10 to about 25% by weight of said outermatrix, said inner matrix, and said methantheline bromide in thecomposition.
 19. The method for preparing the sustained releasepharmaceutical composition of claim 1 which comprises: A. entrapping themethantheline bromide in an inner matrix in an amount at leastsufficient for the total dosage requirement during a treatment period;B. the inner matrix being a water-insoluble but water-swellablehydrophilic polymer of a monomer mixture containing: